A Randomized, Placebo-Controlled Dose-Comparison Trial of Haloperidol for Psychosis and Disruptive Behaviors in Alzheimer’s Disease

Devanand, D. P.; Marder, Karen; Michaels, K.; Sackeïm, Harold A.; Bell, Karen L.; Sullivan, Maria A.; Cooper, Thomas B.; Pelton, Gregory H.; Mayeux, Richard

doi:10.1176/ajp.155.11.1512

Cited by 206 publications

(108 citation statements)

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“…s2 receptor activation. Although it is difficult to extrapolate from our cell-based data to the human condition, the exacerbation of psychomotor, behavioral and cognitive dysfunction by typical antipsychotics, including HAL, both in healthy elderly volunteers and in Alzheimer disease patients 24,44 may reflect s receptorsensitive cascades, for example, a compromised s1 receptor system and/or an activated s2 receptor system (present study and Gil-Ad et al 45 ). Support for this is limited, but recent animal studies suggest that s1 receptor agonists may be useful in alleviating learning and memory impairment in aged rats or mice, or in rodents injected centrally with the Alzheimer-related peptide b-amyloid (Ab) (see Phan et al 46 and references therein).…”

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confidence: 68%

“…Thus, DTG influences a priori the apoptotic component (B15%) and not the VitE-sensitive (oxidative stress) component of HAL- Haloperidol promotes toxicity of the Alzheimer disease-related peptide b-amyloid (1-40) Haloperidol can exacerbate behavioral and psychomotor dysfunction in patients with Alzheimer disease. 24 We examined whether Bcl-XS might be implicated in this event. The concentrations of HAL (100 mM) and of the Alzheimer disease-related peptide Ab40 (30 mM) are not significantly toxic over the treatment interval (Figure 7) (confirms previous observations; for HAL, see above, while demonstrable Ab40 toxicity requires a longer interval, see Mousseau et al 25 ).…”

Section: Haloperidol Induces Both (S-sensitive) Apoptosis and (S-insementioning

confidence: 99%

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Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Wei

Dai

et al. 2006

Pharmacogenomics J

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Toxicity of the typical antipsychotic haloperidol (HAL) comprises an apoptotic component that we link to pro-apoptotic Bcl-XS in PC12 preneuronal and N2a neuroblastoma cells. The mitochondrial translocation of Bcl-XS and its interaction with the pore-forming voltage-dependent anion channel (VDAC) correlates with the redistribution of cytochrome c and the cleavage of Poly(ADP-ribose) polymerase. Haloperidol-induced apoptosis is mediated by the sigma2 (s2) receptor system and does not involve the expected antagonism of the dopamine D 2 receptor, nor is it influenced by Vitamin E-or p53/Bax-mediated events. Pathological relevance is demonstrated by the cytotoxic synergism between HAL and the Alzheimer diseaserelated peptide b-amyloid(1-40), which correlates with Bcl-XS expression and its interaction with VDAC, and with cytosolic cytochrome c translocation. These data provide for a unique apoptotic mechanism that could underscore the clinical risks associated with HAL, particularly following chronic regimens or in the elderly.

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mentioning

confidence: 68%

Section: Haloperidol Induces Both (S-sensitive) Apoptosis and (S-insementioning

confidence: 99%

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Wei

Dai

et al. 2006

Pharmacogenomics J

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“…86 Since that review, only one further randomized, placebocontrolled trial has been published. 87 In that study "standard" dose haloperidol (2-3 mg/day) was significantly better than "low" dose haloperidol (0.5-0.75 mg/day) or placebo for the treatment of psychosis and psychomotor agitation in A D . Response rates ranged from 55-60% with standard doses, 25-35% with low doses of haloperidol, to 25-30% with placebo.…”

Section: Antipsychoticsmentioning

confidence: 90%

Recommendations for the Management of Behavioral and Psychological Symptoms of Dementia

Herrmann

2001

Can. J. Neurol. Sci.

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Suppl. 1 -S96 serious problem that they encountered, rating it more frequently as a serious problem than the memory disturbance itself. The significance of BPSD was recently endorsed by both the United States A l z h e i m e r's A s s o c i a t i o n 6 and the International Psychogeriatric Association 1 as research priorities. The phenomenology and prevalence of BPSD have beenThe behavioral and psychological symptoms of dementia (BPSD) include delusions, hallucinations, misidentifications, agitation, wandering, pacing, restlessness, disinhibition, apathy, negativism, emotional lability, depression, anxiety, sleep disturbance and sexually inappropriate behaviours.1 While not included as diagnostic criteria for dementia by DSM-IV 2 or the NINCDS-ADRDA, 3 behaviours such as paranoia, depression, euphoria and apathy were recognized by Alzheimer in the initial description of the illness that bears his name. 4 Historically, the focus on BPSD began only recently, prompted by an early study by Rabins et al,5 who interviewed caregivers of patients with dementia. While these behaviours were noted in 50-90% of patients, caregivers considered physical aggression the most ABSTRACT: Background: The behavioral and psychological symptoms of dementia (BPSD) are common, serious problems that impair the quality of life for both patient and caregiver. In order to provide recommendations based upon the best available evidence, a qualitative literature review was performed. Methods: A search of the English language medical literature published between 1966 and 2000 was performed. The quality of the studies was assessed by considering the subjects, trial design, analysis and results. Final recommendations were based upon the quality of available evidence. Results: The management of BPSD begins with a thorough assessment to search for underlying causes of behaviour change. Concomitant medical illness should be treated and sensory impairment ameliorated. Nonpharmacological approaches should be instituted prior to medication use. These interventions include music, light, changes in level of stimulation and specific behavioral techniques. Antipsychotics are the best studied pharmacological intervention for agitation and aggression and have demonstrated modest but consistent efficacy. Antidepressants such as trazodone and selective serotonin re-uptake inhibitors, as well as anticonvulsants such as carbamazepine and valproic acid have also demonstrated efficacy. Benzodiazepines can be used for short-term treatment as p.r.n. agents when necessary. Pharmacotherapy must be monitored closely for both effectiveness and side effects, with consideration of medication withdrawal when appropriate. Conclusion: The management of BPSD can significantly improve the quality of life for the patient and caregiver. Their assessment and management are essential components of the treatment of dementia.RÉSUMÉ: Recommandations pour la prise en charge des symptômes comportementaux et psychologiques de la démence. Introduction: L e s symptômes comportementaux et ...

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“…Previous studies of haloperidol [18] and trazodone [19] in similar populations, however, suggest that study design issues may have influenced the ability to observe treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

Regression to the Mean: Implications for Clinical Trials of Psychotropic Agents in Dementia

Cummings¹,

Tractenberg²,

Gamst³

et al. 2004

CAR

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Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer's disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD.This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms.Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups.Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials. REGRESSION TO THE MEAN: IMPLICATIONS FOR CLINICAL TRIALS OF PSYCHOTROPIC AGENTS IN DEMENTIARandomized controlled trials (RCT) are necessary to establish the efficacy of potentially useful pharmacologic agents. In the past ten years, RCT have been employed in assessing In clinical trials addressing neuropsychiatric symptoms in AD, robust changes have been observed in patients in the placebo group [2,3]. In contrast to other disorders where such responses have been intensively studied, there have been no previous investigations of the placebo-group changes in RCTs involving patients with AD. True placebo effects, regression to the mean, and treatment benefit from participating in a clinical trial may all contribute to placebo group responses. A recent randomized clinical trial 5 found no difference between placebo, pharmacotherapy, and behavioral therapy in the treatment of agitation in AD; all groups improved. This trial is of particular importance since it is the only multicenter trial conducted comparing pharmacologic and nonpharmacologic instruments in AD. To investigate the observations made in this trial, we conducted a post hoc analysis of the response in the placebo group. We investigated patient characteristics (dementia severity, dementia duration and characteristics of the behavioral abnormalities), caregiver characteristics (gender, age, education), and trial characteristics (site and time of entry of the patient into the trial) to identify potential predictors of the response observed in the placebo group. We also assessed the timing of the response in the different trial groups and examined the p...

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A Randomized, Placebo-Controlled Dose-Comparison Trial of Haloperidol for Psychosis and Disruptive Behaviors in Alzheimer’s Disease

Cited by 206 publications

References 48 publications

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

Recommendations for the Management of Behavioral and Psychological Symptoms of Dementia

Regression to the Mean: Implications for Clinical Trials of Psychotropic Agents in Dementia

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